Hathorn et al.

Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

RESEARCH

Open Access

The effectiveness of gentamicin in the treatment

of Neisseria gonorrhoeae: a systematic review
Emma Hathorn1*, Divya Dhasmana1, Lelia Duley2 and Jonathan DC Ross1

Abstract
Background: A high level of resistance in Neisseria gonorrhoeae has developed against penicillins, sulphonamides,
tetracyclines and quinolones, and recent surveillance data have shown a gradual reduction in sensitivity to current
first-line agents with an upward drift in the minimum inhibitory concentration of ceftriaxone. Laboratory sensitivity
testing suggests that gentamicin, an aminoglycoside, may be an effective treatment option for gonorrhoea
infection when used as a single intramuscular dose.
Methods: A search of electronic reference databases and grey literature was used to identify randomised trials and
well-conducted prospective studies with concurrent controls evaluating single-dose gentamicin against placebo or
a comparator regimen in the treatment of uncomplicated gonorrhoea infection in men and women aged 16 years
and over. The primary outcome was microbiological cure of N. gonorrhoeae.
Results: Eight hundred and thirty-nine studies were identified, of which five (1,063 total participants) were included.
All five studies administered single-dose gentamicin via intramuscular injection to men with uncomplicated gonococcal
urethritis. Three studies were randomised trials, one was quasi-randomised and one was non-randomised but included
a comparator arm. Comparator antibiotics included an alternative aminoglycoside or antibiotic used in the syndromic
management of male urethritis. Methodology was poorly described in all five included studies. The high risk of bias
within studies and clinical heterogeneity between studies meant that it was inappropriate to pool data for
meta-analysis. Cure rates of 62% to 98% were reported with gentamicin treatment. The relative risk of cure
was comparable between gentamicin and comparator antibiotics.
Conclusions: The studies identified provide insufficient data to support or refute the efficacy and safety of
single-dose intramuscular gentamicin in the treatment of uncomplicated gonorrhoea infection. Additional randomised
trials to evaluate gentamicin for this indication are therefore required.
Systematic review registration: PROSPERO CRD42012002490
Keywords: Gonorrhoea, Neisseria gonorrhoeae, Gentamicin, Treatment

Background
Gonorrhoea, caused by Neisseria gonorrhoeae, is the
second most common bacterial sexually transmitted
infection in the UK. The number of gonorrhoea diagnoses continues to rise with latest data indicating a 52%
increase in England from 16,835 to 25,525 infections
between 2010 and 2012 [1]. The highest rates of infection are found in residents of urban areas, and infection
is concentrated in core groups such as young people and
* Correspondence: emma.hathorn@nhs.net
1
Whittall Street Clinic, University Hospitals Birmingham, Birmingham B6 4DH,
UK
Full list of author information is available at the end of the article

men who have sex with men (MSM). Of male diagnoses

in 2012, 42% were reported in MSM and 55% of heterosexual diagnoses were in those aged 15 to 24 years [1]. A
number of factors, in addition to continuing levels of
unsafe sexual behaviour, may have contributed to the
observed increase in diagnosis of gonorrhoea including
the introduction of highly sensitive nucleic acid amplification tests (NAATs), the introduction of self-testing
including extra-genital sites (pharyngeal and rectal sites
in MSM), an increase in sexual health screening following the roll-out of the National Chlamydia Screening
Programme, and improvements in reporting and surveillance. However, the rise in incident infection reported

2014 Hathorn et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

in the UK mirrors the global trend; the World Health

Organization (WHO) estimates gonorrhoea to represent
106.1 million of the 498.9 million new cases of curable
sexually transmitted infections (syphilis, chlamydia, gonorrhoea and trichomoniasis) worldwide [2].
N. gonorrhoeae are intracellular gram-negative bacteria
transmitted via sexual contact. They primarily infect the
mucous membranes of the urethra, endocervix, rectum,
pharynx and conjunctiva. Infection of the genital tract
causes local inflammation that can result in dysuria, discharge, genital discomfort and pain. Infection in women
may spread to the fallopian tubes and ovaries causing
pelvic inflammatory disease (PID). Complications include
infertility, chronic pelvic pain and ectopic pregnancy and
can result in considerable physical and emotional morbidity in addition to a significant financial burden on healthcare services [3,4]. An estimate of the average lifetime
costs for women who develop complications is $6,350
for chronic pelvic pain, $6,840 for ectopic pregnancy and
$1,270 for infertility [4].
Gonorrhoea has consistently been identified as a risk
factor for incident HIV infection in both heterosexual
and MSM populations [5-7]. This is thought to result
from increased HIV viral shedding in genital secretions
[8,9] and from an increased concentration of target cells
for HIV in the locally inflamed mucosa found in individuals with gonorrhoea [10]. Ensuring effective gonorrhoea
testing and treatment is therefore important to both reduce the global incidence of curable sexually transmitted
infections and control the spread of HIV.
Testing guidance advocates the use of NAATs to detect
gonorrhoea [11-14]. These tests benefit from high sensitivity and specificity, quick turnaround times, ability to
use non-invasive specimens from patients and permitting
dual screening for chlamydia and gonorrhoea at extragenital sites. However, to allow antibiotic susceptibility
testing, a sample for culture is also required. In vitro
susceptibility testing is used to guide individual patient
management in addition to providing data for surveillance
programmes. Antibiotic resistance in N. gonorrhoeae is a
continuing problem, and surveillance of antibiotic resistance with a change in empirical treatment when resistance
occurs in >5% of isolates is recommended [15]. This is of
particular importance in resource-limited settings where
testing for N. gonorrhoeae is difficult and individuals are
typically treated using syndrome-based algorithms.
A high level of resistance in N. gonorrhoeae has
developed against penicillins, sulphonamides, tetracyclines and fluoroquinolones, which are now no longer
recommended for use. Current guidelines recommend
a single dose of intramuscular ceftriaxone with or without the addition of a single oral dose of azithromycin
for the treatment of uncomplicated gonorrhoea infection [12,14,16,17]. The European Centre for Disease

Page 2 of 9

Prevention and Control (ECDC) has proposed a working

case definition for confirmed treatment failure that includes both clinical and laboratory criteria [18]. The
precise resistance breakpoint for cephalosporin antibiotics
is unknown, but surveillance data from the gonococcal
isolate surveillance projects in both the UK and US
have reported an upward drift in the mean inhibitory
concentration (MIC) of ceftriaxone (UK: 13% with MIC
over 0.03 mg/l in 2010 cf. 1% in 2007 [19]; US: 0.05% with
MIC over 0.125 mcg/ml in 2006 cf. 0.5% in 2010 [20]).
Clinical failure of cephalosporins has now been reported
in Japan and Europe [21-23].
The mechanism of resistance to cephalosporin antibiotics is not fully understood. Plasmid-mediated resistance
has not been observed, but a number of chromosomal
mechanisms, including the presence of mosaic penA genes
and mutations in penA, penB, mtrR promoter and mtrR
genes, have been reported. Mosaicism of the penA gene
that encodes penicillin-binding protein 2 (PBP2) is thought
to be the predominant mechanism causing cephalosporin
resistance. Penicillin-binding proteins are involved in the
synthesis of peptidoglycan, a major component of bacterial
cell walls. Mosaic sequences of PBP2, resulting from recombination events involving penA gene sequences from
other Neisseria species, have been identified in clinical isolates that demonstrate reduced susceptibility to cefixime
and ceftriaxone [24-26]. Options to treat gonorrhoea if
cephalosporins become ineffective are severely limited.
Gentamicin, an aminoglycoside antibiotic, is known to
be clinically effective in the treatment of gram-negative
infections, exerting both a bacteriostatic and bactericidal
effect. It is an inexpensive antibiotic and has been used
successfully to treat genital gonorrhoea infections in
resource-limited settings. Studies in Malawi have shown
high susceptibility of gonococcal isolates to gentamicin
in vivo and clinical cure rates of approximately 95% when
used in combination with doxycycline [27,28]. Whilst it is
not included in current UK or European gonorrhoea treatment guidelines, an evaluation of gentamicin susceptibility
of gonorrhoea isolates across 17 European countries was
performed in 2009 in response to the emergence of
decreased susceptibility to third-generation, extendedspectrum cephalosporins. The majority of MICs for genital and rectal isolates fell within a narrow range: 95% of
isolates within 48 mg/l and 79% of isolates demonstrating an MIC of 8 mg/l [29]. Cephalosporin-resistant gonococci are unlikely to exhibit cross-resistance to gentamicin
given its bacteriostatic action via the bacterial ribosome in
contrast to the action of cephalosporins on bacterial cell
wall synthesis. Administration of gentamicin is limited to
either the intravenous or intramuscular routes, and the
optimal dose for uncomplicated genital infections is not
known. However, a single intramuscular injection of antibiotic lends itself to outpatient management and may

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

reduce the risk of vestibular and renal toxicity that is seen

with extended high trough drug concentrations.
In view of concerns about decreasing sensitivity of N.
gonorrhoeae to current first-line agents, there is a clear
need to identify treatment options. This systematic review assesses the clinical effectiveness and safety of gentamicin for the treatment of N. gonorrhoeae.

Methods
The review protocol was registered with PROSPERO
(CRD42012002490) [30].
Criteria for considering studies for the review
Types of study

Randomised controlled trials, quasi-randomised trials

and prospective studies with concurrent controls and
consistent treatment assignment were eligible for inclusion. Studies with historical controls, before and after
studies, case series and case reports were excluded.

Page 3 of 9

Search strategy for identification of studies

Electronic searches

A search strategy was developed and used to identify relevant studies (Additional file 1). Databases were searched
on 11th May 2012 and 27th July 2012 and updated on
2nd June 2014 as follows: MEDLINE from PubMed 1950
to present, Embase 1980 to present, CINAHL 1981 to
present, CAB Abstracts, EThOS and the Cochrane Central Register of Controlled Trials. Searches were repeated
of www.clinicaltrials.gov and www.who.int/trialsearch to
identify ongoing trials. Papers published in peer-reviewed
journals, theses, conference abstracts and reports were
included. No language restriction was placed on the
search strategy.
Searching other resources

Searches were repeated in grey literature to identify any

unpublished and ongoing research (Additional file 1).
References from included studies were reviewed for further relevant studies.

Types of participants

Studies recruiting men and women aged 16 years or over

receiving their first antibiotics as an inpatient or outpatient for a microbiological diagnosis of gonorrhoea at
any anatomical site were included. Gonorrhoea was diagnosed by microscopy, culture or nucleic acid amplification tests.

Data collection and analysis

Study selection

Two reviewers (DD and EH) independently screened titles

and abstracts against the inclusion criteria to identify eligible citations. Disagreements were resolved by discussion.
Full-text copies were obtained if insufficient information
was available and of all studies meeting inclusion criteria.

Types of intervention

Studies in which gentamicin was given at any single dose

intramuscularly or intravenously were eligible for inclusion. To enable assessment of gentamicin efficacy, studies in which gentamicin was given as part of a combined
antibiotic regimen were excluded. Comparators included
no treatment, placebo or any alternative antibiotic given
either orally or parenterally.
Types of outcome

Primary outcome The primary outcome is microbiological cure of N. gonorrhoeae (negative microscopy,
culture or nucleic acid amplification test).
Secondary outcomes The secondary outcomes are the
following:
 Clinical resolution of symptoms (dysuria, genital

discharge, genital pain or abdominal pain).

 Need for additional antibiotic therapy.
 Adverse events (rash, allergy, injection site

discomfort, renal dysfunction, hearing loss,

vestibular dysfunction, other reported adverse events
attributed to antibiotic).
 Hospital attendance (admission to hospital,
unscheduled clinic attendance).

Data extraction

A standardised data extraction form was developed and

utilised. Data were independently extracted from the studies, and discrepancies were resolved by discussion and
consultation with a third reviewer if necessary.
Assessment of risk of bias

Risk of bias in studies was assessed using the risk of bias

tool described in the Cochrane Handbook for Systematic
Reviews of Interventions [31]. A bias judgement (low
risk of bias, high risk of bias or unclear risk of bias) was
allocated to each of six domains (sequence generation,
allocation of sequence concealment, blinding, incomplete outcome data, selective reporting bias and other
bias) within the tool. The tool was developed for assessment of randomised trials, and the Good Research for
Comparative Effectiveness (GRACE) checklist, which
has been utilised to rate the quality of observational
studies of comparative effectiveness, was used to assess
non-randomised studies included for data analysis [32].
Data synthesis

Characteristics, main findings and risk of bias assessment were tabulated for each study. Levels of attrition
were noted for included studies. If data were adequate

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

Page 4 of 9

for meta-analysis, we planned that results be presented

as a summary risk ratio with 95% confidence intervals,
on an intention-to-treat basis.
Reviewing the studies identified a high level of clinical
heterogeneity. The dose of gentamicin varied from 160
to 280 mg, and the primary assessment of cure was
based on symptoms, microscopy and culture or was not
reported. The definition and assessment of risk of reinfection was not reported in some studies [33-35], and
those with potential re-exposure were excluded in one
study [36]. Meta-analysis was considered to be inappropriate due to these methodological differences and the
results summarised in a tabular format.

Description of studies

Results
Eight hundred and thirty-nine studies were identified by
the search strategy (Figure 1). Two reviewers independently screened all titles and available abstracts. Nineteen
studies were discussed due to disagreement, of which 17
were excluded, as they did not meet pre-specified inclusion criteria. Seventeen full-text articles were retrieved
and 12 were excluded after further review.
Five studies with a total of 1,063 participants were included in the review: three randomised trials [28,33,34],
one quasi-randomised trial [36] and one non-randomised
study with a comparator arm [35].

Assessment of risk of bias

Table 1 summarises the characteristics of the included

studies. All five studies included men with uncomplicated gonococcal urethritis diagnosed by culture [34],
identification of gram-negative diplococci on urethral
smear [36] or a combination of Gram-stained urethral
smear and culture [28,34,36]. Five hundred and twentynine men received intramuscular gentamicin in a single
dose160 mg (n = 20), 240 mg (n = 207) or 280 mg (n =
302). No study compared gentamicin to placebo and
comparator antibiotics included an alternative aminoglycoside (kanamycin and spectinomycin) or antibiotic used
in the syndromic management of male urethritis.

The included studies were assessed for risk of bias using

either the Cochrane risk of bias tool (randomised studies) or the GRACE checklist (observational studies).
Study methodology was poorly reported, so that consistently assessing methodological quality and risk of bias
in each individual study was difficult. Insufficient detail was often included in the publication to distinguish
accurately what was done in contrast to what was reported. As such, risk of bias within and across individual
studies was unclear or judged by reviewers to be high
(Additional file 2).

839 records retrieved

from all searches

79 duplicates removed
760 tles/abstracts
screened against
eligibility criteria

19 studies discussed due to reviewer

disagreement
-17 not thought to meet eligibility
criteria aer discussion

17 full-text arcles
retrieved for review

12 arcles excluded:
-No comparator arm (n=5)
-Gentamicin given in combinaon (n=1)
-Laboratory based in vitro studies (n=2)
-Unable to obtain full text (n=4)

5 studies included in
quantave analysis

Figure 1 Review profile.

Author

Methods

Participants

Intervention

Primary outcome

Gentamicin

Comparator

Men with uncomplicated

gonorrhoea infection
(gram-negative diplococci
on urethral smear), Lusaka,
Zambia

Single-dose
gentamicin 280 mg
intramuscular
injection (n = 302)

Single-dose kanamycin 2 g
Cure
intramuscular injection (n = 113)

Iskandar et al. RCT (randomly

(1978) [33]
allocated to 3
groups of 30
patients)

Men with acute

gonorrhoea infection
(gonorrhoea on Gram stain
of urethral smears), Egypt

Single-dose
gentamicin 240 mg
intramuscular
injection (n = 30)

Pareek and
Chowdhury
(1981) [35]

Non-randomised,
comparator study

Men with urethral

gonorrhoea infection
(culture positive and beta
lactamase detected),
Riyadh, Saudi Arabia

Yoon et al.
(1988) [34]

RCT (random
numbered tickets
used to divide
patients into
2 groups)

Lule et al.
(1994) [28]

RCT (computerised
randomisation)

Hira et al.
(1984) [36]

Quasi-random
(treatment assigned
to alternate
consecutive patients)

Evaluation of re-infection
All patients advised to abstain
from sexual activity for 2 weeks
after therapy.

Patients in whom N. gonorrhoea

persisted or re-appeared (as
determined by a positive result of
a smear or culture) in the absence
of sexual activity during the
follow-up period were considered
to be treatment failure

Patients excluded if reported sexual

activity during 2 weeks follow-up
period with or without persistent
or re-appearing gonorrhoea on
culture

Co-trimoxazole (Bactrim,
Roche) 8 tablets daily divided
into 2 doses for 2 days (n = 30).
Trimethoprim-sulphametrol
(Lidaprim, Ciba) 8 tablets
divided into 2 doses for 2 days
(n = 30)

Cure

One case of re-infection reported

in which there was a history of
re-exposure.

Cases with negative smears plus

resolution of discharge on day 7
were considered cured

Safe sex advice and assessment

of re-infection not described

Single-dose
gentamicin 160 mg
intramuscular
injection (n = 20)

Single-dose spectinomycin
2 g intramuscular injection
(n = 20)

Cure

Safe sex advice, definition and

assessment of re-infection not
described

Men with uncomplicated

gonococcal urethritis (Gram
stain and bacteriological
test of urethral secretions),
Seoul, Korea

Single-dose
gentamicin 240 mg
intramuscular
injection (n = 137)

Single-dose kanamycin 2 g
intramuscular injection
(n = 137)

Cure

Men presenting with urethral

discharge +/dysuria and
gram-negative intracellular
diplococci on urethral smear
and/or positive
culture, Malawi

Single-dose
gentamicin 240 mg
intramuscular
injection (n = 40)

Amoxicillin 3 gm, probenecid To determine the relative

1 gm, and clavulanate
contribution of gonorrhoea and
125 mg by mouth once
chlamydia to urethritis in Malawi
(n = 60)

Safe sex advice not described

Amoxicillin 3 gm, probenecid To evaluate the effectiveness of

1 gm, and clavulanate
five antibiotic therapies for
125 mg, by mouth once and urethritis
doxycycline 100 mg BD for
7 days (n = 56)

6/48 (12.5%) patients with

persistent gonococcal infection
at follow-up reported having sex
between initial and follow-up
visits compared to 21 of 249
(8.4%) men for whom gonococcal
infection was not detected at
follow-up (p = 0.4)

Ciprofloxacin 250 mg by
mouth once (n = 59)

RCT randomised control trial, mg milligrams, g grams, BD twice daily.

All patients advised to avoid

sexual intercourse during the
Cases with negative Gram stain
period of treatment. Definition
and bacteriological test
and assessment of re-infection
(undefined) of urethral secretions
not described

Cure not defined. An assessment

of symptoms and signs, urethral
Gram stain and culture were
obtained at 810 days post
treatment

Page 5 of 9

Co-trimoxazole (trimethoprim
320 mg/sulphamethoxazole
1,600 mg) by mouth for
2 days (n = 29)

Patients in whom culture on

days 3, 7 and 14 post treatment
were negative were considered
cured

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

Table 1 Characteristics of included studies

Outcome

Hira et al. [36]

Iskandar et al. [33]

Pareek and Chowdhury [35]

Yoon et al. [34]

Lule et al. [28]

Cure

Gentamicin: 98% (216/220)

Gentamicin: 27/30 (90%)

Gentamicin: 19/20 (95%)

Gentamicin: 78/125 (62.4%)

Gentamicin: 38/40 (95%)

Kanamycin: 95% (85/89)

Co-trimoxazole: 29/30 (96.6%)

Spectinomycin: 16/20 (80%)

Kanamycin: 86/126 (68.3%)

Ciprofloxacin: 55/59 (93%)

23 patients did not

attend follow-up and were
excluded

APC: 40/60 (67%)

Lidaprim: 29/30 (96.6%)

Adjusted to include only
those attending on day 7:
Gentamicin: 19/22 (86.4%)

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

Table 2 Outcome data of included studies

APC-D: 52/56 (93%)

Co-trimoxazole: 14/29 (48%)

Bactrim: 15/16 (93.7%)

Lidaprim: 20/21(95.2%)
Need for additional treatment

No data

No data

No data

No data

No data

Adverse event

No serious toxicity or other adverse

reactions were noticed in either group
of men. Serum creatinine values were
normal in the 52 patients given
gentamicin and the 28 kanamycin
whose blood samples were tested

No adverse side effects

were observed in any
of the patients

There were no obvious side

effects with either of these
drugs. The blood urea and
creatinine values remained
within normal limits

There was no side effect

of using kanamycin and
gentamicin

No data

Hospital attendance

No data

No data

No data

No data

No data

APC amoxicillin, probenecid and clavulanate, APC-D amoxicillin, probenecid, clavulanate and doxycycline, TMPSMX trimethoprim/sulphamethoxazole.

Page 6 of 9

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

Page 7 of 9

Favours comparator

Favours gentamicin

10

0.
1

Lule 1994 (TMPSMX)

Lule 1994 (APC-D)
Lule 1994 (APC)
Lule 1994 (Ciprofloxacin)
Pareek 1981 (Spectinomycin)
Iskander 1978 (Bactrim)
Iskander 1978 (Lidaprim)
Yoon 1988 (Kanamycin)
Hira 1985 (Kanamycin)

Risk Ratio (log 10 scale)

Figure 2 Efficacy of gentamicin. The probability of cure following treatment with gentamicin compared to cure with a comparator antibiotic. The
probability of cure was comparable between gentamicin and comparator antibiotics. TMPSMX trimethoprim/sulphamethoxazole, APC amoxicillin,
probenecid and clavunate, APC-D amoxicillin, probenecid, clavunate and doxycycline. Risk ratios: Lule (TMPSMX) 1.9679 (95% CI 1.3412-2.8873); Lule (APC-D)
1.0231 (95%CI 0.924201.1325); Lule (APC) 1.4250 (95% CI 1.1754-1.7275); Lule (ciprofloxacin) 1.0191 (95% CI 0.9231-1.1251); Pareek (specinomycin) 1.1875
(95% CI 0.9331-1.5113); Iskander (Bactrim) 0.9310 (95% CI 0.8122-1.0672); Iskander (Lidaprim) 0.9310 (95% CI 0.8122-1.0672); Yoon (kanamycin) 0.9142
(95% CI 0.7630-1.0954); Hira (kanamycin) 1.0280 (95% CI 0.979301.0791).

Effectiveness of gentamicin

All five studies reported cure, as defined in Table 1, as a

primary outcome (Table 2). Fixed effects meta-analysis
was not performed for any of the defined outcomes due
to the high level of clinical heterogeneity between studies and the high risk of bias within individual studies
(Additional file 2). Whilst cure, presented as a percentage
rate, was reported in each of the included studies, they differed significantly in definition of cure (clinical cure or
negative microscopy and/or culture), timing of cure and
their assessment of re-infection (Additional file 3).
Figure 2 summarises the efficacy of gentamicin in the
treatment of uncomplicated gonorrhoea infection. The
probability of cure was comparable between gentamicin
and comparator antibiotics.

Discussion
Our systematic review found insufficient data to support
or refute the role of gentamicin in the treatment of gonorrhoea infections. Five studies of single-dose intramuscular
gentamicin for the treatment of uncomplicated gonococcal
urethritis in men met inclusion criteria and reported cure
rates of 62% to 98%. The probability of cure was comparable between gentamicin and comparator antibiotics.
A separate systematic review assessing the effectiveness of
gentamicin for uncomplicated urogenital gonorrhoea infection has recently been published [37] and reported a pooled
percentage with negative culture after single-dose gentamicin of 91.5% (95% CI 88% to 94%). It included three studies
of which only two met our inclusion criteria due to methodological differences [36]. Firstly, Dowell and Kirkcaldy included studies with historical controls and single-arm case
series. Secondly, they included studies in which gentamicin

was given as part of a treatment regimen in combination

with other antibiotics. Thirdly, their definition of gonorrhoea
was limited to participants with uncomplicated urogenital
infection and diagnosis was restricted to urethral or cervical
culture at the time of treatment and follow-up.
Our data supports the conclusion that gentamicin may
not achieve the 95% cure rate recommended by the World
Health Organization for empirical therapy. However, the
risk of bias within available studies limits any firm conclusions being drawn and a potential role for gentamicin as
an alternative or adjunctive agent remains and merits
evaluation in randomised trials. Preliminary data from an
American study examining the effectiveness of gentamicin
with azithromycin recently suggested high efficacy (202/
202 negative culture at 1017 days post treatment) but
poor tolerability of this regimen (27.7% reporting nausea
and 47% any gastrointestinal disturbance) [38]. Also, this
study did not determine the efficacy of the individual antibiotics, or efficacy of gentamicin for extra-genital infections, and further randomised control trials incorporating
currently recommended antibiotic regimens, comparing
different gentamicin doses and correlating in vitro gentamicin susceptibilities to clinical response are needed.
A comprehensive review of the literature was performed with all relevant identified articles obtained and
translated. Few studies met the inclusion criteria with
limited numbers of patients receiving single-dose intramuscular gentamicin. The five studies included for data
extraction were performed in Malawi, Zambia, Egypt,
Korea and Saudi Arabia, and their findings may not be applicable to other settings where first-line treatment regimens and gentamicin susceptibility may differ. No studies
of genital infection in women or non-genital gonorrhoea

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

infection were identified by the search strategy, and the

findings cannot be extrapolated to these groups.
Quality of included studies

Two of the identified studies were very small with 20 [35]

and 30 [33] patients receiving gentamicin. The comparator
antibiotic varied across the included studies, and all were
suboptimal when compared to current UK management
guidelines. Two studies were described as randomised control trials, but none adequately described their method of
generating a random allocation sequence, method of concealment or blinding to the allocation schedule. In addition,
differences in definition of gonococcal infection, gentamicin
dosing, comparator antibiotic, evaluation of re-infection
and definition and timing of cure meant that it was
inappropriate to pool data for meta-analysis.

Page 8 of 9

4.
5.

6.

7.

8.

Conclusions
Based on current evidence, there are insufficient data to
support or reject a recommendation for inclusion of singledose gentamicin as a first-line agent in the treatment of uncomplicated gonorrhoea infection. Further high-quality
RCTs incorporating currently recommended antibiotic regimens with laboratory measurement of gentamicin MIC are
needed to inform a change in clinical practice.

9.

Additional files

12.

10.

11.

13.
Additional file 1: Search strategy. Search strategy used to identify
studies for inclusion in the review.
Additional file 2: Risk of bias assessment. Summary of the risk of bias
in each included study.
Additional file 3: PRISMA statement. Checklist against PRISMA
guidelines for the reporting of systematic reviews.
Competing interests
The authors declare that they have no competing interests.
Authors contributions
EH and DD conducted the review and writing of the manuscript. LD
reviewed the protocol, gave statistical advice and reviewed the manuscript.
JDCR contributed to the initial concept and reviewed and revised the
manuscript. All authors read and approved the final manuscript.

14.
15.

16.

17.

18.
Author details
1
Whittall Street Clinic, University Hospitals Birmingham, Birmingham B6 4DH,
UK. 2Nottingham Clinical Trials Unit, Nottingham Health Science Partners,
Queens Medical Centre, Nottingham, UK.

19.

Received: 10 June 2014 Accepted: 8 September 2014

Published: 19 September 2014

20.

References
1. Health Protection England: Sexually transmitted infections and chlamydia
screening in England 2012. Health Prot Rep 2013, 7(23):821.
2. World Health Organization: Global incidence and prevalence of selected
curable sexually transmitted infections, 2008. [http://www.who.int/
reproductivehealth/publications/rtis/stisestimates/en/]
3. Aghaizu A, Adams EJ, Turner K, Kerry S, Hay P, Simms I, Oakeshott P:
What is the cost of pelvic inflammatory disease and how much could
be prevented by screening for Chlamydia trachomatis? Cost analysis of

21.

22.

the Prevention of Pelvic Infection (POPI) trial. Sex Transm Infect 2011,
87(4):312317.
Yeh JM, Hook EW, Goldie SJ: A refined estimate of the average lifetime
cost of pelvic inflammatory disease. Sex Transm Dis 2003, 30(5):369378.
Venkatesh KK, van der Straten A, Cheng H, Cheng H, Montgomery ET, Lurie
MN, Chipato T, Ramjee G, Blanchard K, Padian NS, Mayer KH, de Bruyn G:
The relative contribution of viral and bacterial sexually transmitted
infections on HIV acquisition in southern African women in the methods
for improving reproductive health in Africa study. Int J STD AIDS 2011,
22(4):218224.
Watson-Jones D, Baisley K, Weiss HA, Tanton C, Changalucha J, Everett D,
Chirwa T, Ross D, Clayton T, Hayes R: Risk factors for HIV incidence in
women participating in an HSV suppressive treatment trial in Tanzania.
AIDS 2009, 23(3):415422.
Pathela P, Braunstein S, Blank S, Schillinger J: HIV incidence and time to
diagnosis among men with bacterial rectal infections, New York City.
Sex Transm Infect 2011, 87(Suppl 1):A184.
Cohen MS, Hoffman IF, Royce RA, Kazembe P, Dyer JR, Daly CC, Zimba D,
Vernazza PL, Maida M, Fiscus SA, Eron JJ Jr: Reduction of concentration of
HIV-1 in semen after treatment of urethritis: implications for prevention
of sexual transmission of HIV-1: AIDSCAP Malawi Research Group.
Lancet 1997, 349(9069):18681873.
Ghys PD, Fransen K, Diallo MO, Ettigne-Traor V, Coulibaly IM, Yebou KM,
Kalish ML, Maurice C, Whitaker JP, Greenberg AE, Laga M: The associations
between cervicovaginal HIV shedding, sexually transmitted diseases and
immunosuppression in female sex workers in Abidjan. Cote dIvoire AIDS
1997, 11(12):F85F93.
Levine WC, Pope V, Bhoomkar A, Tambe P, Lewis JS, Zaidi AA, Farshy CE,
Mitchell S, Talkington DF: Increase in endocervical CD4 lymphocytes
among women with nonulcerative sexually transmitted diseases. J Infect
Dis 1998, 177(1):167174.
HPA Guidance for gonorrhoea testing in England and Wales, 2010.
[http://www.bashh.org/BASHH/Guidelines/Guidelines/BASHH/Guidelines/
Guidelines.aspx]
Bignell C: European (IUSTI/WHO) guideline on the diagnosis and
treatment of gonorrhoea in adults. Int J STD AIDS 2009, 20(7):453457.
Smith DW, Tapsall JW, Lum J: Guidelines for the use and interpretation of
nucleic acid detection tests for Neisseria gonorrhoea in Australia: a
position paper on behalf of the Public Health Laboratory Network.
[http://www.health.gov.au/internet/main/publishing.nsf/Content/cdacdi2904-pdf-cnt.htm/$FILE/cdi2904b.pdf]
CDC Sexually Transmitted Diseases Guidelines, 2010: gonococcal infections.
[http://www.cdc.gov/std/treatment/2010/gonococcal-infections.htm]
World Health Organization: Guidelines for the management of
sexually transmitted diseases. [http://www.who.int/hiv/pub/sti/en/
STIGuidelines2003.pdf]
Bignell C, FitxGerald M: UK national guideline for the management of
gonorrhoea in adults, 2011. [http://www.bashh.org/BASHH/Guidelines/
Guidelines/BASHH/Guidelines/Guidelines.aspx]
Government of South Australia, Communicable Disease Control Branch:
Revision of treatment guidelines for uncomplicated gonorrhoea.
[http://www.health.wa.gov.au/diseasewatch/vol17_issue3/gonorrhoeaetreatment.cfm]
European Centre for Disease Prevention and Control: Response plan to
control and manage the threat of multi-drug resistant gonorrhoea in
Europe. [http://www.ecdc.europa.eu/en/publications/Publications/1206ECDC-MDR-gonorrhoea-response-plan.pdf]
HPA GRASP 2010 Report. [http://webarchive.nationalarchives.gov.uk/
20140714084352/http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/
1316016752917]
CDC 2010 STD Surveillance Report: Gonorrhoea. [http://www.cdc.gov/std/
stats10/gonorrhea.htm]
Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S, Iwasaku K, Nakayama S,
Kitawaki J, Unemo M: Is Neisseria gonorrhoeae initiating a future era of untreatable
gonorrhea?: detailed characterization of the first strain with high-level resistance
to ceftriaxone. Antimicrob Agents Chemother 2011, 55(7):35383545.
Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P:
High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae
in Europe (France): novel penA mosaic allele in a successful
international clone causes treatment failure. Antimicrob Agents
Chemother 2012, 56(3):12731280.

Hathorn et al. Systematic Reviews 2014, 3:104

http://www.systematicreviewsjournal.com/content/3/1/104

Page 9 of 9

23. Carnicer-Pont D, Smithson A, Fina-Homar E, Bastida MT: First cases of

Neisseria gonorrhoeae resistant to ceftriaxone in Catalonia, Spain,
May 2011. Enferm Infecc Microbiol Clin 2012, 30(4):218219.
24. Ameyama S, Onodera S, Takahata M, Minami S, Maki N, Endo K, Goto H,
Suzuki H, Oishi Y: Mosaic-like structure of penicillin-binding protein 2
gene (penA) in clinical isolates of Neisseria gonorrhoeae with
reduced susceptibility to cefixime. Antimicrob Agents Chemother 2002,
46(12):37443749.
25. Ito M, Deguchi T, Mizutani KS, Yasuda M, Yokoi S, Ito S, Takahashi Y, Ishihara
S, Kawamura Y, Ezaki T: Emergence and spread of Neisseria gonorrhoeae
clinical isolates harboring mosaic-like structure of penicillin-binding protein
2 in Central Japan. Antimicrob Agents Chemother 2005, 49(1):137143.
26. Tanaka M, Nakayama H, Huruya K, Konomi I, Irie S, Kanayama A, Saika T,
Kobayashi I: Analysis of mutations within multiple genes associated with
resistance in a clinical isolate of Neisseria gonorrhoeae with reduced
ceftriaxone susceptibility that shows a multidrug-resistant phenotype.
Int J Antimicrob Agents 2006, 27(1):2026.
27. Brown LB, Krysiak R, Kamanga G, Mapanje C, Kanyamula H, Banda B,
Mhango C, Hoffman M, Kamwendo D, Hobbs M, Hosseinipour MC,
Martinson F, Cohen MS, Hoffman IF: Neisseria gonorrhoeae antimicrobial
susceptibility in Lilongwe, Malawi, 2007. Sex Transm Dis 2010, 37:169172.
28. Lule G, Behets FM, Hoffman IF, Dallabetta G, Hamilton HA, Moeng S, Liomba
G, Cohen MS: STD/HIV control in Malawi and the search for affordable
and effective urethritis therapy: a first field evaluation. Genitourin Med
1994, 70(6):384388.
29. Chisholm SA, Quaye N, Cole MJ, Fredlund H, Hoffmann S, Jensen JS, van de
Laar MJ, Unemo M, Ison CA: An evaluation of gentamicin susceptibility
of Neisseria gonorrhoeae isolates in Europe. J Antimicrob Chemother 2011,
66(3):592595.
30. Hathorn E, Dhasmana D, Dule L, Ross J, Harding J: The effectiveness of
gentamicin in the treatment of Neisseria gonorrhoeae: a systematic
review. PROSPERO: International Prospective Register of Systematic
Reviews. 2012: CRD42012002490. [http://www.crd.york.ac.uk/
NIHR_PROSPERO/]
31. The Cochrane Collaboration: Chapter 8: Assessing risk of bias included
studies. [http://handbook.cochrane.org/]
32. Dreyer NA, Velentgas P, Westrich K, Dubois R: The GRACE checklist for
rating the quality of observational studies of comparative effectiveness:
a tale of hope and caution. JMCP 2014, 20(3):301308.
33. Iskandar IO, Nahuib F, Gabry L EL: A comparative study of gentamicin,
co-trimoxazole and trimethoprim-sulphametrol in acute gonococcal
urethritis. J Egypt Med Assoc 1978, 61:489495.
34. Yoon JY, Kim YT, Kim JH: Treatment of uncomplicated male gonococcal
urethritis: kanamycin vs. gentamicin. Korean J Dermatol 1988, 26(2):184188.
35. Pareek SS, Chowdhury MNH: Comparative study between gentamicin and
spectinomycin in the treatment of infections to penicillin-resistant
gonococci. Curr Ther Res 1981, 30(2):177180.
36. Hira SK, Attili VR, Kamanga J, Mkandawire O, Patel JS, Patel MI: Efficacy of
gentamicin and kanamycin in the treatment of uncomplicated
gonococcl urethritis in Zambia. Sex Transm Dis 1985, 12(1):5254.
37. Dowell D, Kirkcaldy RD: Effectiveness of gentamicin for gonorrhoea
treatment: systematic review and meta-analysis. Sex Transm Inf 2012,
88:589594.
38. Kirkcaldy RD: Treatment of gonorrhoea in an era of emerging
cephalosporin resistance and results of a randomised trial of new
potential treatment options. Sex Transm Infect 2013, 89:A14A15.
doi:10.1136/sextrans-2013-051184.0043.
doi:10.1186/2046-4053-3-104
Cite this article as: Hathorn et al.: The effectiveness of gentamicin in the
treatment of Neisseria gonorrhoeae: a systematic review. Systematic
Reviews 2014 3:104.

Submit your next manuscript to BioMed Central

and take full advantage of:
Convenient online submission
Thorough peer review
No space constraints or color gure charges
Immediate publication on acceptance
Inclusion in PubMed, CAS, Scopus and Google Scholar
Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit